COMMENTARY

Understanding the Brain

Jeffrey A. Lieberman, MD

Disclosures

September 30, 2014

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Hello. This is Dr Jeffrey Lieberman of Columbia University, speaking to you today for Medscape. I want to discuss an exciting initiative that was launched by the U S government last year, which I believe holds great importance for all of brain science and medicine but particularly for psychiatry. This is President Obama's human BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies). The purpose of this effort is to accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures that show how individual brain cells and complex neural circuits interact at the speed of thought.

The immediate reaction of many psychiatrists was, "Oh, my goodness. This is a big initiative focusing on technology and brain function at the cellular, molecular level. What will it mean for me and how I treat my patients? How will it help with understanding human behavior and psychopathology?"

In addition, many psychiatric researchers, upon hearing this thought, said, "Oh, my goodness. Here is a new initiative focusing on basic science and technology that will suck up existing resources that, in turn, will not be available for the translational or applied research that can produce results that will benefit me and my patients in the very near future."

On closer examination of what the BRAIN Initiative really involves and what its goals are, I believe that of all the medical disciplines and all the scientific disciplines, psychiatry will benefit most from this innovative initiative. I believe this because the problems we deal with in psychiatry—mental disorders, disturbances in behavior, and how those derive from brain function—have been the most challenging for biomedical research to disentangle and understand, so that we can identify the causes, treatments, and cures. For a long time, we thought this was because psychiatry and the brain behavioral sciences were not making progress in the same way as in other medical specialties, such as infectious diseases, cardiology, and cancer, and the surgery subspecialties, such as orthopedics and ophthalmology.

Extraordinary Complexity of the Brain

In reality, however, the slow and more deliberate progress was actually a result the extraordinary complexity of the organ that we needed to study. When you think about it, the brain is orders of magnitude more complicated than any other organ in the body. The heart is an important organ, but it is basically a muscle with four chambers and tubes to pump blood. The lung is a respiratory mechanism. The kidneys are a filter and an excretory system. And if you look at any part of these organs, they look very similar to other parts.

But as anatomists such as Jeff Lichtman have very elegantly demonstrated, the brain is uniquely complex and specialized in function. It comprises more than 200 billion different types of cells and has more than 30 trillion types of synapses by which these cells connect with each other.

In addition, in the brain, just as in real estate, it is all about location. One area of the brain is not the same as another area of the brain, and each has specialized functions relating to its anatomic location and structure.

Thus, it is no wonder that it took us a long time to be able to deconstruct the brain. History has shown us that technology has been a rate-limiting factor for knowledge and progress, particularly in the sciences. Copernicus may have developed a mathematical model of heliocentrism, but Galileo had to develop a microscope before it could be proved. Pasteur could not have discovered microorganisms and the cause of disease before microscopes were available.

Similarly, the human genome could not have been sequenced until we had the technologies to be able to produce high-throughput sequencing of large amounts of DNA. Brain science, particularly as it relates to behavior, has the same limitations. The BRAIN Initiative is squarely focused on developing this next generation of technologies.

How This Helps Psychiatry

In addition, this initiative should be very beneficial for psychiatry and studies of mental illness because the brain functions we are concerned with are the most highly evolved functions in the animal kingdom. They are not functions involved with basic maintenance of vital functions or motor activity, but they involve perception, emotion regulation, thought, creativity—the functions that make us uniquely human. To understand these functions is more challenging.

When we think about neurologic disorders, we think of disorders that, to a significant degree, are caused by specific types of lesions or specific types of pathologies affecting discrete structures. With mental illness and behavioral disturbances, we are talking about disturbances not in actual structure but in the functionality of cells, and more specifically the circuits that these cells form. Nowadays, we commonly say that mental disorders are, in effect, "connectopathies," in which complex pathologic mechanisms are affecting these distributed circuits and large numbers of cells that comprise these circuits.

How will the human BRAIN Initiative address these problems? In the latter part of the 20th century, with the advent of psychopharmacology, genetics imaging, and neuroscience, psychiatry became focused more on the brain than the mind. This led to an effort to apply these disciplines to understand brain systems and functions as they related to behavior and mental illness.

It became clear, however, that in order to appreciate the real-time activity of distributed circuits involving hundreds of thousands, or tens of hundreds of thousands of cells, we need better, more sophisticated, more powerful technology than simply the MRI and PET scans and the ability to do in vivo recording in animal models. Even though these are tremendous breakthroughs and powerful technologies, they are insufficient. We need the next generation of these technologies. I believe the human BRAIN Initiative will address the challenges we face more than any other discipline.

A List of Priorities

In order to jump-start this process, Francis Collins, Director of the National Institutes of Health, impaneled an advisory committee and asked this group to produce an interim report. The interim report was delivered in June 2014 and has been accepted by the Institute. It is important to remember that the focus of the Initiative is not on technology per se, but on the development and use of tools to acquire fundamental insights into how nervous system functions, health, and disease specifically support and influence complex functions, such as behavior.

The advisory committee has identified a series of priorities to enable scientists to better analyze the way in which neural circuits function and interact with each other in real time. The committee has identified nine priorities:

1. To generate the capacity to define a census of cell types in order to characterize all cell types in the nervous system.

2. To create structural maps of the brain —that is, to map the connected neurons in local and distributed brain circuits.

3. To develop new, large-scale network recording capabilities—in animals, and noninvasively in humans—that will enable us to record the dynamic neuronal activity from complete neural networks in various areas, in real time, over long periods . To this end, to develop entirely new technologies for neural recording that will be based on existing methods, such as optogenetics and molecular genetics, and nanoscience, but also extending beyond these.

4. To develop a suite of tools for circuit manipulation so that different neural circuits can be perturbed to see what functions they alter and how the circuits interact.

5. To link neuronal activity to behavior, not simply by recording and making inferences but to have direct ability to connect these manipulations of neural circuits to specific behaviors.

6. To develop the theoretical modeling and statistical capability, the computational capability, to integrate all of this information. This will be a tremendous challenge.

7. To delineate mechanisms underlying human imaging technologies. That is, to take the existing technologies and make them even more powerful in terms of spatial and temporal resolution so that they can provide a better understanding of the cellular mechanisms underlying these commonly measured signals in the brain that we now measure with our MRI and PET technologies.

8. To create mechanisms to enable collection of human data. On a large scale, how can we take the data that are collected every day in routine clinical studies and enable them to be used to address scientific questions?

9. To disseminate this knowledge, and to train researchers and then clinicians in how to use it and apply it to the study of the illnesses of concern to them.

Even though this seems to be a very technological and basic- science–oriented initiative, I believe that we in clinical psychiatry and mental healthcare providers stand to be the greatest beneficiaries. This effort has the potential to push us over the threshold toward developing technologies that can match the complexity of the human brain.

We can only wait to learn whether this proves to be the case, but I am sure it will result in tremendous progress, regardless of what the ultimate level of success of this initiative is.

The real goal of this initiative is to measure the fluctuating patterns of electrical chemical activity flowing within cells and circuits of the brain over time and space, and to understand how their interplay creates unique mental and behavioral activities. Even if we are not focused on research and neuroscience in any fundamentally basic way but function primarily as clinicians, I believe this is something we can all be excited about and look forward to with great interest.

This is Dr Jeffrey Lieberman of Columbia University in New York City, speaking to you today for Medscape.

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